New 6 alpha-methyl-19-nor-progesterone and a process of its manufacture

ABSTRACT

The present invention provides the new 3,20-dioxo-6 Alpha methyl-17 Alpha -caproyloxy-19-nor- Delta 4-pregnene. It may be used as gestagen and for fertility control.

Unified States Pateni [111 3,759,962

Anner et a1. Sept. 18, 1973 1 NEW 6 [56] References Cited ALPHA-METHYL-l9-NOR-PROGESTERONE UNITED STATES PATENTS AND A PROCESS OF ITS MANUFACTURE 2,891,079 6/1959 Dodson et al 260/39714 [75] Inventors: Georg Anner; Jaroslav Kalvoda, 3,061,616 10/1962 Camerino et al. 260/397.4 both f Basel, Switzerland 3,455,903 7/1969 Shroff 260/2393 7 3,488,346 1/1970 Dorfman et al 260/239.55 [73] Asslgnee: Ciba-Gelgy Corporation, A sley, 3,644,440 2 1972 Douglas et al. 260/3974 N.Y. 3,655,649 4/1972 Habermehl et al. 260/2395 22 F'l d: 4 7 l 1 1e July I l9 2 Primary Examiner-Henry A. French [211 Appl. No.: 271,874 Attorney-Joseph G. Kolodny Related U.S. Application Data [62] Division or s", N0. 78,581, 06:. 6, 1970. ABSTRACT The present invention provides the new 3,20-dioxo-6a- [30] Foreign Application lriority Data methyl-l7a-caproyloxy-l9-nor-A-pregnene.

0C. 10, 1969 Switzerland 15272/69 It may be used as gestagen and for fertility onn-0L 52 s. Cl 260 3914, 260/2395 0, 424/243 1 Claim, N0 Drawings [51] Int. Cl. C07c 169/34 [58] Field of Search mm/Machine Sei'ched Steroids NEW 6 ALPHA-METHYL-lQ-NOR-I'ROGESTERONE AND A PROCESS OF ITS MANUFACTURE This is a division, of application Ser. No. 78,581, filed Oct. 6, I970.

i5 CHa The present invention provides a new 6a-methyl-l9-nor-progesterone of the formula OHa CH3 -"OC0-(CH2)4CH3 as well as a process for its manufacture, and pharmeceutical preparations containing the new compound.

The new compound possesses valuable pharmacological properties. inter alia, it has more especially a high progestative and ovulation-inhibiting activity and can therefore be used above all as gestagen and for fertility control. I

The high activity of the new compound can be demonstrated in animal tests; thus the 3,20-dioxo-6amethyl- 1 7a-caproyloxyl Q-nOr-N-pregnene products, for example, in the Clauberg test on rabbits a complete progestative effect on a single subcutaneous administration of 0.1 to 1 mg/kg. The ovulation-inhibiting effect can be proved, for example, by way of the inhibition of the spontaneous ovulation of the rat, which materializes on subcutaneous administration of as little a dose as 0.003 to 0.03 mg/kg/day and on peroral administration of a dose from 0.01 to 0.3 mg/kg/day.

The new compound may be obtained in the known manner, when (l) in a compound of the general formula in which R, represents a free or ketalized oxo group,

for example the ethylenedioxy group; R represents a (III) Y K3 (J II:

10 the double bond starting from the carbon atom in the in which R and R have the meanings defined above,

water is eliminated; or 4. in a compound of the general formula CHI-A in which R,, R and R have the meanings defined above and A represents a nitrogen atom linked with at least two radicals, the Cl'l -A group is reduced to the methyl group, and any enol or ketal grouping present in a resulting compound is split to form the corresponding keto group, and/or a. free l7-hydroxyl group possibly present'in a resulting compound is caproylated, and the 6a-methyl compound is isolated from the resulting epimer mixture at any desired stage of the process, if I desired after first having enriched the 6a-epimer.

As mentioned above, these reactions are carried out in the known manner. Thus, for reducing the aldehyde group in a compound of the formula II, a palladium catalyst, for example palladium carbon, is preferably used, in the presence of a hydrogen donor, for example cyclohexene. When the reaction is carried out in this manner, the 3-enolether or 3-enolester grouping is split at the same time.

On the other hand, the double bond starting from the carbon atom in 6-position (see formula ill) is advantageously reduced with catalytically activated hydrogen, such as hydrogen in the presence of a palladium catabonate.

The elimination of water from a compound of the formula IV to form the double bond can be achieved with an inorganic or organic base, such as potassium tertiary butylate, potassium tertiary amylate, potassium carbonate, triethylamine or collidine, or with an inorganic acid, for example hydrochloric. sulphuric or perlyst, for example palladium carbon or palladium carchloric acid, or with an organic acid such as acetic, propionic, oxalic or trifluoracetic acid. During this dehydration it is possible, for example, by treatment with a strong acid, to split an esterified hydroxyl group in the l7-position hydrolytically to the free hydroxyl group, or when the reaction is performed in a suitable organic, acidic medium, for example in an acid anhydride, especially in a mixed acid anhydride, a possibly present free l7-hydroxyl group can be esterified.

In a compound of the formula V the symbol A represents a nitrogen atom linked to at least two radicals; preferably, it is a di-lower alkylamino, a lower alkylaralkylamino or an alkylene-amino group whose alkylene residue may be interrupted by oxygen, sulphur or a further nitrogen atom, being a pyrrolidino, piperi dino, morpholino, thiomorpholino or piperazino group, or an acid addition salt thereof, a complex salt with boron or a quanternary ammonium derivative thereof. These amino and ammonium compounds can be reduced hydrogenolytically with hydrogen in the presence of a catalyst, for example Raney nickel, palladium or platinum or palladium carbon, in the presence of a hydrogen donor, such as cyclohexene or an alcohol.

An enol or ketal grouping possibly present in a resulting compound is hydrolyzed in the usual manner, for example with a (preferably inorganic) acid, such as hydrochloric, sulphuric or perchloric acid or a strong organic acid, for example trifluoracetic acid or sulphonic acid, for example para-toluenesulphonic acid.

In a resulting compound the l7-hydroxyl group may be caproylated, depending on the starting material used. When the acid residue does not correspond to the caproyl group, the esterified hydroxyl group is hydrolysed in the usual manner with an acid or preferably with a base, to form the free hydroxyl group. A free hydroxyl group present is then esterified in the usual manner with capronic acid or with a functional derivative thereof, such as its halides or anhydrides.

A resulting compound is generally a mixture of the 60:- and 6B-epimers. This mixture is difficult to separate, but by treatment with an acid, which treatment, if desired, may be performed within the main or an additional process, the oa-form can be enriched, and this enriched form is easier to isolate by chromatography and crystallization.

The above-mentioned reactions are carried out in the usual manner in a suitable solvent, with cooling or heat- The invention includes also any variant of the present process in which an intermediate obtained at any stage of the process is used as starting material and any remaining step(s) is/are carried out, or a starting material is formed in situ or used in form of a salt or other derivative thereof.

The starting materials are known or, insofar as they are new, they can be prepared in the known manner; thus, for example, a compound of the formula ll is accessible from an enolester of a 3,20-diketo-l7-R' -N- nor-pregnene by formulation with the Vilsmeyer reagent, for example from phosphorus oxychloride, phosgene or thionylchlorate and dimethylformamide, for example in methylenechloride. When the intermediate from the Vilsmeyer reaction is reduced directly, for example with sodium borohydride in pyridine, compounds of the formula V are obtained.

The resulting 6-formyl-3-enolester or -ether can be reduced to the '-hydroxymethylene compound which can be converted into the compound of the formula ill by treatment with an acid.

The compounds of the formula N can be prepared, for example, from corresponding 5,6-epoxy-6- desmethyl compounds by reaction with a methyl- Grignard compound.

The new compounds can be used as medicaments in the form of pharmaceutical preparations which contain the new active substances in conjunction or admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable for enteral, for example oral, or parenteral administration. Suitable excipients are substances that do not react with the new compounds, such as water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees or capsules, or in liquid form solutions, suspensions (especially microsuspensions) or emulsions. They may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain further therapeutically valuable substances.

The new preparations contain, for example for oral administration, advantageously in the form of tablets, dragees or capsules, preferably 1 to mg, advantageously 5 to 50 mg, of the active substance per unit dose. The dose in which the new preparations is given depends on the requirements of the individual patient.

The preparations are manufactured in the way known for the formulation of medicaments.

The invention includes also the use of the said active substances or of the preparations containing these active substances as gestagens or for fertility control.

The following Examples illustrate the invention.

EXAMPLE l 2.0 Grams of palladium carbon (10 percent Pd) are pasted with 4 ml of glacial acetic acid; after about 5 minutes the whole is filtered, washed neutral with methanol, and transferred into the reaction vessel with about 10 ml of methanol. Then 10.0 g of 3-methoxy-6- formyll 7a-caproyloxy-20-oxo-A -l 9-norpregnadiene and 20 ml of freshly distilled cyclohexene are added and the whole is stirred and refluxed for 18 hours. The reaction mixture is cooled to room temperature, filtered off the catalyst, mixed with 7.4 g of magnesium silicate, refluxed for l5 minutes, one more cooled, diluted with ether, filtered and evaporated under a water-jet vacuum. The resulting crude product (9.1 g) is dissolved in 100 ml of toluene and chromatographed on 50 times its own weight of silica gel. From the first fractions ooz-methyl-l7a-caproyloxy-l9-norprogesterone is eluted with a 90:10-mixture of toluene and ethyl acetate. After several recrystallizations from methylenechloride+ether the compound melts at 1 13 to C.

The formyl compound used as starting material is prepared, for example, thus: 13.0 Grams of 17acaproyloxy-l9-nor-progesterone are dissolved in ml of benzene; then about 25 ml of solvent are distilled off, 6.5 ml of freshly distilled o-formic acid methyl ester, 0.65 ml of methanol and l30 mg of p-toluenesulphonic acid are added and the whole is stirred and refluxed for 2% hours. Then, within 30 minutes, a fur ther postion (10 ml) of the solvent are distilled off, the

mixture is cooled, mixed with 1.3 ml of pyridine and diluted with ether, washed with saturated sodium hydrogencarbonate solution and then with water, dried and evaporated under a water-jet vacuum. Crystallization of the residue from methanol, in the presence of small quantities of pyridine, furnishes 3-methoxy-17acaproyloxy-20-oxo-A"' -19-nor-pregnadiene.

10.0 Grams of this compound are dissolved in 25 ml of methylenechloride and at 6C dropped into the Vilsmeyer reagent prepared at C from 5.8 g of dimethylformamide and 3 ml of phosphorus oxychloride in 20 ml of methylenechloride. The red solution is stirred for 2 hours at 0C and allowed to rise within 1 hour to 18C, then once more cooled to about C; a suspension of 22 g of anhydrous sodium acetate in 70 ml of 90 percent methanol is added and the whole is stirred for 30 minutes at room temperature. The batch is then diluted with water and methylenechloride, the organic layer is washed successively twice with water, once with a potassium carbonate solution of 4 percent strength and once with water; then the washings are extracted with methylenechloride, dried and evaporated under a water-jet vacuum.

The resulting crude 3-methoxy-6-formyl-l7acaproyloxy- 20-oxo-A -l9-nor-pregnadiene (ultraviolet spectrum: A 220 e 000 and m 14 500) is reduced without first having been purified.

EXAMPLE 2 85 ml of ethyl acetate are prehydrogenated in the presence of 100 mg of a 5 percent palladium-calcium carbonate catalyst. After addition of 1.2 g of 3,20- dioxo-6 methylene- 1 7a-caproyloxy-N- l 9-norpregnene, the mixture is hydrogenated at room temperature until 70 ml (0C/760mm) of hydrogen have been absorbed. The catalyst is subsequently filtered off, given a final wash with ethyl acetate and the filtrate evaporated under a water-jet vacuum. The pure 3,20- dioxo-6a-methyl-17a-caproyloxy-- -A-l9-nor-pregnene, which melts at 1 13-1 15C, is obtained from chromatography of the resulting crude product on silica gel and subsequent repeated recrystallisation from a methylene chloride-ether-petroleum ether mixture.

The 6-methylene compound that serves as starting material can be manufactured as follows:

From a suspension of 10 g of 3,20-dioxo-l7acaproyloxy--A-l9-nor-pregnene in 125 ml of absolute benzene, approx. 15 ml of solvent are distilled off within 10 minutes. 5.0 ml of o-formic acid methyl ester, 0.5 ml of methanol and 100 mg of p-toluene sulphonic acid are added and the mixture refluxed for 3 hours. Within 30 minutes a further ml of solvent are distilled off, the reaction mixture is cooled to approx. 20C, 1.5 ml of pyridine are added and the whole is distilled with ether and worked up in the usual way. Crystallisation of the crude product from an etherpetroleum ether mixture yields the pure 3-methoxyl7a-acetoxy-20-oxo-A -19-nor-pregnadiene. 4.64 g of a solution of the above enol ether, cooled to 0C, in 15 ml of methylene chloride is added dropwise to a Vilsmeier compound, prepared at -80C from 2.95 ml of dimethylformamide and 1.45 ml of phosphorous oxychloride in 10 ml of methylene chloride. The red solution is stirred for 2 hours at 0C and afterwards heated to room temperature within 1 hour. The reaction mixture is cooled once more to approx. 5C, 10 g of sodium temperature.

acetate in portions and 35 ml of percent methanol are added and the batch is stirred for 45 minutes at room temperature, diluted with water and worked up with methylene chloride in the usual way. 1.8 g of the so obtained 6-formyl compound are dissolved in 20 m1 of methanol and stirred for 15 minutes at room temperature after addition of 180 mg of sodium boric anhy- .dride. The reaction solution is then poured onto 200 ml ice water and extracted twice with ether. The organic phase is washed with water until neutral, dried, and evaporated under a water-jet vacuum. Then 1.4 g of the crude reduction production are dissolved in 14 ml of 66 percent strength acetic acid and stirred for 5 minutes at room temperature. The reaction mixture is poured onto 250 ml of ice water, the precipitate that settles out taken up in ether, washed with ice-cold diluted sodium hydrogen carbonate solution and with water until neutral. The washings are extracted with ether, the organic solutions dried with sodium sulphate and evaporated under a water-jet vacuum at approx. 25-30C bath The resulting crude 3,20-dioxo-6- methylene-17a-caproyloxy-A--l9-nor-pregnene can be subjected to hydrogenation without having been purified.

EXAMPLE 3 2.0 g of 3,20-dioxo-6a-methyl-l7a-hydroxy-N-19- norpregnene are suspended in 5 m1 of capronic acid with passage of nitrogen and while stirring, and mixed dropwise within 30 minutes with 2.5 ml of trifluoro'acetananhydride. The reaction mixture is subsequently stirred for a further 4 hours at room temperature, then poured onto approx.10 g of ice water, and the mixture subjected to steam distillation in order to separate the excess capronic acid. The non-volatile solid residue'is taken up in ether, and the ether solution exhaustively washed with ice-cold diluted sodium hydroxide solution and water. The washings are extracted with ether, the organic solutions dried and evaporated under a water-jet vacuum. The resulting crude product is purified by chromatography on silica gel and subsequent repeated recrystallisation from a methylene chloride-ether-petroleum ether mixture and yields the 3,20- dioxo-6a-methyl-17a-caproy1oxy-N-l9-nor-pregnene, which melts at 112 to 1 15C and is identical with the product obtained in Example 1.

The 3,20-dioxo-6-methyl-17a-hydroxy-N-l9-norpregnene can be manufactured in the following way:

Asolution of 8.6 g of 3-oxo-5 a,17a-dihydroxy-6B- methyl-20,20-ethylenedioxy-l9-nor-pregnene (obtained from 17a-acetoxy-19-nor-progesterone by successive enolacetylation, sodium boric anhydride reduction, hydrolysis of the 17a-acetoxy group, selective acetylation in 3 position, epoxidation of the A -double bond with m-chloro-perbenzoic acid and Grignard reaction with methyl magnesium iodide) in ml of chloroform and 860 ml of methanol is mixed, while stirring, within 1 minute with 300 ml of N-sodium hydrox-.

ide solution and stirred for 40 minutes at room temperature in atmosphere of nitrogen. The reaction mix-ture is poured onto water, extracted twice with chloroform, the extracts washed with water until neutral, dried, and evaporated under a water-jet vacuum. The resulting crude product is dissolved in 500 ml of acetone and 250 ml of chloroform, mixed with 12.5 ml of a solution prepared by diluting 4.60 ml of concentrated sulphuric acid to 20 ml, and stirred for 40 minutes at room tem- EXAMPLE 4 Oily injection solution Ingredients: 3,20-dioxo-6a-methyI-17a-caproyloxy- I9-nor-A-pregnene 100 mg benzyl benzoate 350 mg benzyl alcohol 90 mg sesame oil. to make 1.0 ml.

The active substance is dissolved in a mixture of benzyl benzoate and benzyl alcohol at 40C, and the clear solution is stirred and mixed with sufficient sesame oil heated at 40C to produce a content of 100.0 mg of active substance in 1 ml of solution. The solution is filtered sterile in the usual manner and chargedinto ampoules under aseptic conditions.

EXAMPLE 5 Oily injection solution I Ingredients: 3 ,20-dioxo-6a-methyl- I 7a-caproyloxyl9-nor-A-pregnene 30.0 mg benzyl alcoho 90.0 mg sesame oil, to make 10 ml.

The active substance is dissolved at 40C in benzyl alcohol. Sufficient sesame oil heated at 40C is stirred into the clear solution to produce a content of 30.0 mg of active substance per 1 ml of solution. The solution is filtered sterile in the usual manner and charged into ampoules under aseptic conditions.

EXAMPLE 6 Injection suspension Ingredients: 3 ,20'dioxo-6a-m ethyll 7B-caproyloxyl9-nor-A-pregnene 10.0 mg sodium carboxymethyl cellulose of medium viscosity 5.0 mg sodium chloride 7.5 mg primary sodium phosphate 1.5 mg secondary sodium phosphate 1.5 mg polyvinylpyrrolidone 0.5 mg sodium ethylmercurithiosalicilate 002mg distilled water, to make 1.0 ml.

The sterile microcrystals of the active substance are suspended under aseptic conditions in the previously prepared and sterilized vehicle. The homogeneous suspension is charged under aseptic conditions into the previously heat-sterilized 1 ml ampoules and closed so that each ml of suspension contains 10.0 mg of active substance.

EXAMPLE 7 Hormone tablet Ingredients per tablet: 3 ,ZO-dioxo-Ga-methyl-17B-caproyloxy- I9-n0r-N-pregnenc 5.0 mg lactose 80.0 mg Aerosil 7.0 mg wheat starch 46.0 mg talcum 6.3 mg magnesium stearate 0.7 mg

Total: 145.0 mg

First, the active substance is homogenously mixed with part of the lactose. This pro-mixture is then mixed with the remaining lactose, the aerosil and part of the starch, moistened with water and in the usual manner granulated and dried.

The remaining starch, the talcum and magnesium stearate are mixed into the dry granulate and the homogeneous mixture is made up in tablets weighing 145.0 mg each.

EXAMPLE 8 Oily injection solution Ingredients:

3,20-dioxo-6a-methyl-I7a-caproyloxy- 19-nor-progesterone 20. g benzyl alcohol 90.0 mg sesame oil, to make 1.0 ml.

The active substance is dissolved in the benzyl alcohol at 40C and into the clear solution sufficient sesame oil heated at 40C is stirred to produce a content of 20.0 mg of active substance per ml of solution. The solution is filtered sterile and under aseptic conditions charged into ampoules in the usual manner.

We claim: 1. The

progesterone.

6a-methyl- I 7a-caproyloxyl 9-nor- 

